The present invention is directed to phenyl compounds substituted with a fused-heterobicyclo moiety. In particular, this invention is directed to phenyl compounds substituted with a fused-heterobicyclo moiety which are metabotropic glutamate receptor—subtype 5 (“mGluR5”) modulators useful in the treatment of psychiatric and mood disorders such as, for example, schizophrenia, anxiety, depression, and panic, as well as in the treatment of pain, Parkinson's disease; cognitive dysfunction, epilepsy, drug addiction, drug abuse, drug withdrawal and other diseases.
A major excitatory neurotransmitter in the mammalian nervous system is the glutamate molecule, which binds to neurons, thereby activating cell surface receptors. Such surface receptors are characterized as either ionotropic or metabotropic glutamate receptors. The metabotropic glutamate receptors (“mGluR”) are G protein-coupled receptors that activate intracellular second messenger systems when bound to glutamate. Activation of mGluR results in a variety of cellular responses. In particular, mGluR1 and mGluR5 activate phospholipase C, which is followed by mobilizing intracellular calcium.
Modulation of metabotropic glutamate receptor subtype 5 (mGluR5) is useful in the treatment of diseases that affect the nervous system (see for example W. P. J. M Spooren et al., Trends Pharmacol. Sci., 22:331–337 (2001) and references cited therein). For example, recent evidence demonstrates the involvement of mGluR5 in nociceptive processes and that modulation of mGluR5 using mGluR5-selective compounds is useful in the treatment of various pain states, including acute, persistent and chronic pain [K Walker et al., Neuropharmacology, 40:1–9 (2001); F. Bordi, A. Ugolini Brain Res., 871:223–233 (2001)], inflammatory pain [K Walker et al., Neuropharmacology, 40:10–19 (2001); Bhave et al. Nature Neurosci. 4:417–423 (2001)] and neuropathic pain [Dogrul et al. Neurosci. Lett. 292:115–118 (2000)].
Further evidence supports the use of modulators of mGluR5 in the treatment of psychiatric and neurological disorders. For example, mGluR5-selective compounds such as 2-methyl-6-(phenylethynyl)-pyridine (“MPEP”) are effective in animal models of mood disorders, including anxiety and depression [W. P. J. M Spooren et al., J. Pharmacol. Exp. Ther., 295:1267–1275 (2000); E. Tatarczynska et al, Brit. J. Pharmacol., 132:1423–1430 (2001); A. Klodzynska et al, Pol. J. Pharmacol., 132:1423–1430 (2001)]. Gene expression data from humans indicate that modulation of mGluR5 may be useful for the treatment of schizophrenia [T. Ohnuma et al, Mol. Brain. Res., 56:207–217 (1998); ibid, Mol. Brain. Res., 85:24–31 (2000)]. Studies have also shown a role for mGluR5, and the potential utility of mGluR5-modulatory compounds, in the treatment of movement disorders such as Parkinson's disease [W. P. J. M Spooren et al., Europ. J. Pharmacol. 406:403–410 (2000); H. Awad et al., J. Neurosci. 20:7871–7879 (2000); K. Ossawa et al. Neuropharmacol. 41:413–420 (2001)]. Other research supports a role for mGluR5 modulation in the treatment of cognitive dysfunction [G. Riedel et al, Neuropharmacol. 39:1943–1951 (2000)], epilepsy [A. Chapman et al, Neuropharmacol. 39:1567–1574 (2000)] and neuroprotection [V. Bruno et al, Neuropharmacol. 39:2223–2230 (2000)]. Studies with mGluR5 knockout mice and MPEP also suggest that modulation of these receptors may be useful in the treatment of drug addiction, drug abuse and drug withdrawal [C. Chiamulera et al. Nature Neurosci. 4:873–874 (2001)].
International Patent Publications WO 01/12627 and WO 99/26927 describe heteropolycyclic compounds and their use as metabotropic glutamate receptor antagonists.
U.S. Pat. No. 3,647,809 describes pyridyl-1,2,4-oxadiazole derivatives. U.S. Pat. No. 4,022,901 describes 3-pyridyl-5-isothiocyanophenyl oxadiazoles. International Patent Publication WO 98/17652 describes oxadiazoles, WO 97/03967 describes various substituted aromatic compounds, and WO 94/22846 describes various heterocyclic compounds.
Compounds that include ringed systems are described by various investigators as effective for a variety of therapies and utilities. For example, International Patent Publication No. WO 98/25883 describes ketobenzamides as calpain inhibitors, European Patent Publication No. EP 811610 and U.S. Pat. Nos. 5,679,712, 5,693,672 and 5,747,541 describe substituted benzoylguanidine sodium channel blockers, and U.S. Pat. No. 5,736,297 describes ring systems useful as a photosensitive composition.
However, there remains a need for novel compounds and compositions that therapeutically inhibit mGluR5 with minimal side effects.